DD218094A5 - PROCESS FOR PREPARING ARYLCYCLOBUTYL METHYLAMINES - Google Patents

Abstract

The invention relates to analogous production methods of novel substituted arylcyclobutyl-methylamines which can be used in medicine as a remedy. The aim of the invention is the provision of new, in particular antidepressant acting preparations. Invention task is the development of manufacturing methods for the substituted arylcyclobutyl-methylamine. Compounds of general formula I wherein R1 is a heterocyclic ring having one or more heteroatoms selected from N, O and S and R2, R3 and R4 being the same or different are H, Hal, -CF3, OH, C1 C3-alkyl, alkoxy, alkylthio, phenyl or R2 and R3 together with the carbon atoms to which they are attached form an optionally substituted second benzene ring. The new compounds and their salts or enantiomers are particularly antidepressant.

Description

Berlin, dow 9.3.1934 AP G Of 0/255 228/1 62 9J5 / 12

Process for the preparation of novel arylcyclobutylmethylamines Field of application of the invention

The invention relates to production methods of novel compounds having advantageous therapeutic efficacy, especially - but not exclusively - in the sense of antidepressants.

Well-known technical solutions

Ka have already become some Arylcyclobutylamine known, for example from British Patent No. 973,887, British Patent No. 1,530,172 and from Chem · Abstr "£ 2 232 365 Ind · J. ^u hem _e Section B 1976 14 B 766 and Chem. Abstr · 8 ^ 23678 Arm, Khim _e Zh, 1976 2% (2) 194. However, a direction of action according to the above has not been described.

Object of the invention

ώθ is an object of the invention to develop new effective therapeutics,

Essence of the invention

The invention has for its object to provide processes for the preparation of novel substituted arylcyclobutyl-methylamines. ^ι

 According to the invention, compounds of the formula I are prepared

"4 -2- HR ₁ - 9th AP 62 NH ₂ 3.1984 G 07 G / 255 975/12 228/1 Vv i G R ₃

in which R ₁ corresponds to a heterocyclic ring having one or more heteroatoms selected from W, O and S;

in which R ₂ 1 Ro and R., which may be identical or different, represent H, halogen, trifluoromethyl, hydroxy, a Älkyl group having 1 bia 3 carbon atoms, an alkoxy group having 1 bia 3 carbon atoms, an alkylthio ^ or in which Rp ¹ → ^r t together with the carbon atoms to which they are attached form an optionally substituted second benzene ring;

and pharmaceutically acceptable salts thereof.

R ₁ is a heterocyclic ring which may contain 5 or 6 atoms and which may contain a heteroatom (for example, furyl, thienyl, pyrrolyl, pyridyl, l'etrahydrof uryl or tetrahydrothienyl) or more than one heteroatom, the latter being equal to each other (e.g. Example, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, iriazolyl, tetrazolyl or dithianyl) or may be unequal (for example, thiazolyl). The heterocyclic "ring may be substituted by, for example, one or more alkyl groups

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substituted with 1 to 3 carbon atoms (for example, methyl), as well as it may be substituted by halogen (for example, fluorine or chlorine), hydroxy, alkoxy groups having 1 to 3 carbon atoms (for example, methoxy) or trifluoromethyl. In preferred compounds of formula I, R _{1 represents} a furyl, '^ hienyl, pyridyl, tetrahydrofuryl, dithianyl, methylfuryl, methylpyrrolyl, methylimidazolyl, methylpyrazolyl, methyltetrazolyl or methylthiazolyl group.

If R.sup.1, R.sup.2 or R.sup.3 is a halogen group, this can be represented by fluorine, chlorine, bromine or iodine. When Rp, R or Rg is an alkyl, alkoxy or alkylthio group, then the group contains 1 to 3 carbon atoms (for example methyl, methoxy or methylthioK, if Rg and R- together with the carbon atoms to which they are attached , form a second benzene ring, then that second benzene ring may optionally be halo (for example fluoro, chloro or bromo) or an alkyl group or an alkoxy group having 1 to 3 carbon atoms (for example methyl or methoxy) or the substituents on the second benzene ring form, together with the carbon atoms to which they are attached, a further benzene ring In preferred compounds of the formula I, R "corresponds to a halogen group (preferably a chlorine, Bromo or iodo group) or a methyl group, a methylthio group or a phenyl group and R 1 is H, a halogeno group (preferably a chloro group) or R ₂ and R ₃ together form the carbon atoms , and I e are attached, a benzene ring,

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Forinel I compounds can be converted into compounds of formula II

R

1 9

II

in which, R ₁ - corresponds to a straight or branched chain alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl group having up to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms and in the Rg is a straight-chain alkyl group having 1 to 3 carbon atoms or a formyl group is "compounds of i'ormel II are suitable for the treatment of depression states" When R ^ is an alkyl group, then this can be branched and containing 1 to 4 carbon atoms (for example, methyl, ethyl or isopropyl). When Rc is an alkenyl or an alkynyl group, then the group contains 3 to 6 carbonators (for example, allyl or propynyl). When R ₅ is a cycloalkyl group, then the cycloalkyl- ing From 3 to 7 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) When Rg is an alkyl group, then the group contains from 1 to 3 carbon atoms (for example, methyl, ethyl, or propyl.) In preferred compounds of the formula II

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R _{5 is} methyl and Rg is methyl or formyl.

Compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts are hydrochlorides, maleates, acetates, citrates, fumarates, tartrates, succinates and salts with dicarboxylic amino acids such as aspartic and glutamic acids. Salts of compounds of formula I may be in the form of solvates (for example hydrates).

Compounds of formula I may contain one or more chiral centers. Compounds having a chiral center exist in two enantiomeric forms, and the present invention includes both enantiomeric forms and mixtures thereof. Compounds having two or more chiral centers exist in diastereoisomeric forms, and the present invention includes each of these diastereoisomeric forms and mixtures prepared therefrom.

In therapeutic use, the active compound of formula I can be administered orally, rectally, parenterally or topically; however, it is preferably administered orally. Thus, the therapeutic compositions containing a compound of Formula I may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable excipients which are suitable for use in such compositions are well known in the pharmaceutical arts. The compositions according to the invention can be 0.1 <>. <. 90% by weight of active ingredient. Such compositions are generally formulated in unit dosage form.

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Pharmaceutical compositions containing a pharmaceutically effective amount of a compound of formula I can be used to treat depression conditions in humans. In such a treatment, the amount of compound dor-formula I administered per day in the range of 1 to 1000 mgj is preferably 5 to 50%

Compounds of the formula I can be replaced by the reductive ..; , Amination of ketones of the formula III can be produced

COR.

III

An example of a suitable reductive amination process is the reaction of the ketone with an ammonium salt such as ammonium acetate in the presence of a reducing agent such as sodium cyanoborohydride.

Compounds of formula I can be prepared by the reduction of compounds of formula IV

IV,

R;

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in which

a) Z is a group of the formula -CR ^ NOH or a diaur derived iJater or .Ether corresponds to _{t to} give compounds of the formula I;

b) Z is a group of the formula -CR ₁ SNi in which ¥ represents a metal-containing moiety derived from an organometallic reagent to give compounds of formula I;

Suitable reducing substances for the above reactions are sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride.

In the above section b), Y is preferably MgCl or MgBr derived from a Grignard reagent or Li derived from an organo-lithium compound.

Compounds of the formula I can be obtained by the decarboxylative rearrangement of amides of the formula V, for example under. Use ^; of iodosobenzene bistrifluoroacetate or by means of a Hofmann reaction using bromine in alkaline solution.

CHR. · CONH,

-S

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Compounds of the formula I can be prepared by the decarboxylative rearrangement of acyl azides in the Curtius reaction. The acylazides can be formed, for example, by reaction of acid chlorides of the formula VI with sodium azide.

VI

Compounds of the formula I can be prepared by a Schmidt reaction "which carboxylic acids of formula VII react with hydrazoic acid",

EAR ₁ -GOOH

VII

R.

Compounds of the formula. I, in which R_ is H, can be prepared by hydrolysis, such as, for example, by acid hydrolysis of compounds of formula II in which Rg is formyl.

Compounds of formula II may be prepared from compounds of formula I using methods that hgebiet on the particular F _aG the conversion of primary au secondary or tertiary amines well known aind _e

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In the following, example © is given for suitable processes: '

a) Alkylation of the primary amines of the formula I for the purpose of loading secondary amines of the formula I, for example by a process which includes the steps of protecting the primary amine with a protecting group such as trifluoroacetyl, alkylating with an alkyl halide and protecting the protecting group, for example by hydrolysis;

b) alkylation of the primary amines of the formula I, for example with an alkyl halide for the purpose .Erplement tertiary amines of the formula I ^ in which R ₁ - and R, - equal to each other

a ind;

c) reacting the primary amines of formula I with sodium borohydride and a carboxylic acid of the formula GH ^ (GHp) GOOH (in which a is 0, V or 2) to give secondary amines of the formula I in which R, - is a group of the formula GlL (GH ₂ ) _{a + 1} and Rg is H or to give tertiary amines of the formula I in which both Rp and Rg of a group of formula CH ₃ (GH ₂ ). correspond;

d) reacting the primary amines of the formula I with formaldehyde and formic acid to provide tertiary amines of the formula I, in which both R - and Rg are methyl;

e) Formylating the primary amines of the formula I, for example by reaction with methyl formate for the purpose of providing compounds of the formula I, in which R_ is formyl, and

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for example, by reducing the formamides with lithium aluminum hydride to provide secondary amines of formula I in which R _{5 is} H and Rg is methyl;

f) acylating the primary amines of the formula I, for example by reaction with an acyl chloride of the formula R ₇ GoCl or an anhydride of the formula (R ₇ GO) ₂ O in which Ry corresponds to an alkyl, alkenyl or alkynyl group and by reducing the resulting amide, for example, with lithium aluminum hydride to provide secondary amines of formula I in which R _{1 is} -CH ₂ R ₇ and Rg is H;

g) reacting the primary amines of the formula I with aldehydes of the formula RgCHO in which Rg corresponds to an alkyl, alkenyl or alkynyl group and reducing the resulting imines, for example with sodium cyanoborohydride or - if Rg and R ₁ contain no reducible double bonds - by catalytic hydrogenation for the purpose of providing secondary amines of the formula I in which R _{0 is} -GH ₀ R _a 'and R _{0 is} H;

h) reacting the primary amines of the formula I with ketones of the formula RqGOR ^ q, in which R ~ and R ₁₀ - are the same or different - are alkyl groups or in which Rq and RQ together with the carbon atom to which they are attached · form an alicyclic ring, and reduce the resulting imines, for example with sodium cyanoborohydride or - if R., Rg and R ^ ₀ contain no reducible double bonds - by catalytic hydrogenation for the purpose of providing compounds of formula I ₁ in which

R ^ is H and R _{2 is} a group of formula VIII

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10

GH

VIII

Compounds of the formula I in which the group R _{1 contains} one or more double bonds can, for example, be reduced by catalytic hydrogenation to give compounds of the formula I in which R ₁ corresponds to a saturated heterocyclic group.

The ketones of formula III can be prepared by the hydrolysis of compounds of formula IV wherein Z is -GR ₁ = NH, or they are prepared by the acid hydrolysis of minerals of formula IX

IX ₁

in which Y represents a metal-containing component derived from an organometallic reagent. The imines of formula IX can be prepared by the reaction of said organometallic reagent with cyano compounds of formula X,

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Rr.

Suitable oily / metalloid reagents include Qrignard. Reagents of the formula R ₁ MgX in which X is Gl, Br or I (Y = MgX) and organolithium compounds of the formula R ₁ Li (Ϊ _a Li),

Ketones of Formula III can be prepared by the reaction of carboxylic acid derivatives such as amides or acid halides with an organometallic reagent, for example, by the reaction of an acid chloride of Formula XI

R.,

COGl

XI

with a Gridnard reagent of the formula R ₁ MgX (in which X is CJ.ι Br or I) ~ at low temperatures or by means of the reaction of carboxylic acids of the formula XII

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COOH

XII

with an organometallic reagent such as an organolithium compound of the formula R.Li ₀

Compounds of the formula IV in which Z corresponds to a group of the formula -GR ₁ = NOH or their esters or esters may be prepared by the reaction of hydroxylamine or one of its ethers or esters with ketones of the formula III.

The preparation of compounds of the formula IV in which Z corresponds to a group of the formula -CR ₁ = NY has been described above with respect to compounds of the formula IX.

Amides of the Pormel V can be prepared by the reaction of ammonia with carboxylic acid derivatives such as acid chlorides of formula XIII, or they can be prepared from cyano compounds of formula XV for example by hydration with aqueous acids or by reaction with hydrogen peroxide in the presence of a base become. '

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XIII

Carboxylic acids of the formula VII and XII can be prepared by the hydrolysis - for example the basic hydrolysis - of cyano compounds of the formula XIII or X, respectively. Carboxylic acids of the formula VII can be obtained by the reaction of amides of the formula V with. nitrous acid. Carboxylic acids of the formula XII can be prepared by the reaction of nitrous acid with the amides, which in turn are a) by the reaction of ammonia with carbonic acid derivatives such as, for example, acidic acids of the formula XI or b) by the reaction of cyano compounds of the formula X can be prepared with hydrogen peroxide in the presence of a base.

Cyano compounds of formula X may be prepared by the reaction of cyano compounds of formula XIV

R. - j

CH ₂ CN

XIV

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be prepared with a 1,3-diaubated propane, such as 1,3-dibromopropane and a Baae, such as sodium hydride. "

Cyano-Verb indungen of formula XJII fcönnön from the cyano compounds of the formula XV

XV

by reaction with a halide of the formula R ₁ X (in which X is chlorine, bromine or iodine) in the presence of a Baae such as Lithiumdiiaopropylamid be restyled.

Cyano compounds of formula XV can be further prepared by reacting ketones of formula III with a reagent to introduce a cyano group such as p-toluene-sulfonylmethyl-aocyanide,

Cyano compounds of formula XV can be prepared from cyano compounds of formula X, for example, by the following series of reactions:

a) hydrolysis of the cyano group to form a carboxylic acid of formula XII or Alkoholyae the cyano group in order

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Formation of an ester of a carboxylic acid of the formula XII;

b) reduction of the carboxylic acid or of its derived .tasters, for example with lithium aluminum hydride or ßoran-dimethylsulfide complex to form the corresponding alcohol j

c) replacing the hydroxy group of the alcohol by an outgoing group such as a p-toluenesulfonyloxy group and

d) Set the leaving group by a cyano group.

Acid chlorides of the formulas XI and VI can be prepared by the reaction of carboxylic acids of the formulas XII or VII, for example with thionyl chloride.

The therapeutic efficacy of the compounds of formula I has been established by determining the ability of the compounds to reverse the hypothermic effects of reserpine in the following manner: Male mice of strain Charles River GD1 with a mass of between 18 and 30 grams were in After five hours, the body temperature of each of the mice was measured orally, after which mice were challenged intraperitoneally with reserpine (5 mg / kg) in solution in ascorbic acid (50 mg / ml) containing deionized water injected iSs with a liquid volume of 10 ml / kg of body mass Heun hours after the start of the test the food was withdrawn while water was still available ad libitum ₀ Twenty-four hours after the test

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At the beginning of the period, the mice were exposed to mice and the test compound suspended in deionized water in a 0.10% solution of hydroxyethylcellulose (commercially available under the trade name Celloaize QP 15000 from Union Carbide) in a 10 ml dose volume / kg Körpermaaae administered. Three hours later, the body temperatures of all mice were again measured. The percentage inversion of reserpine-induced loss of body temperature is then calculated according to the formula

- έΐ ai. _x

The mean value for each group of five mice was determined for several doses, thus allowing to obtain a value for that dose which had a 50% inversion (UD50 ) causes. All compounds, which were the end products of the above-described Auaführungsbeiapielea, produced ÜD5.0 values of 30 mg / kg or below ₀ The experts further noted that ea aich hereby to a detection test for compounds with anti-depressant Action in humans, <

The invention will now be illustrated by the following embodiments, which are given by way of example only. All compounds were characterized by conventional analytical techniques and yielded satisfactory data for analysis. Velvet-

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The sohmelt and boiling points are given in degrees centigrade ₀

Embodiment 1

Hypobiophene (10 ml) was added to a solution of butyl lithium in dry oil (60 ml) (prepared by the reaction of lithium (1.8 g) and butylbromide (14 g) followed by filtration through glass wool), followed by mixing Was heated under reflux for 2 h. Was then added dropwise (15 g) was added in dry üither (20 ml), a solution of 1- (4-chlorophenyl) cyclobutane carbonitrile, and the mixture was heated for 75 minutes under reflux conditions "After cooling to -10 ⁰ C a mixture was prepared from Üis and water (30 ml) and then added ice-cold 5N hydrochloric acid (50 ml). Toluene (100 mL) was added, and the mixture was refluxed for 3 hours. The toluene layer was separated, dried, and the solvent was removed by evaporation to give a residue, again at 156 ⁰ G and 0. 5 mm Hg was distilled to give /Ϊ- (4-chlorophenyl) cyclobuty1.7 (thien-2-yl) ketone (m.p. 74 o.107 ⁰ G) »

Mixture of the above-prepared ketone (2.77 g)> formamide (10 ml) and 93% formic acid (2 ml) was heated at 100 ^° C. for 17 hours. The mixture was cooled and extracted with dichloromethane. The extract was washed and dried, and the solvent was removed to afford a O1 which solidified to give N-formyl-Xi- (4-chlorophenyl) cyclobutyl7 (thien-2). yl) methylamine (mp 114 ... 119 ⁰ G).

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The N prepared in the above manner - K'ormyl compound (1.55 g) was added to a Gemisoh from kqnz ^ nfrWerter Sates'äure (1OmI) ₁ Water (10 ml) and diethylene glycol dimethyl ether (20 ml) was added, whereupon the Reaktionagemisoh Was heated to 140 ⁰ G for 30 min. The reaction mixture was poured into water (300 ml), then aqueous sodium hydroxide was added, and the resulting basic mixture was extracted with ether. The Kther extract was washed with water and extracted with 1M hydrochloric acid. The acid extract was washed with Jither, made alkaline with aqueous sodium hydride and extracted with ether. By the dried -h'therextrakt hydrogen chloride gas was passed to T ^ -. (4-Ghlorphenyl) cyclobutyl7 (thien-2-yl) methylamine hydrochloride (m.p. 238.o.240 ⁰ C) to devoted

AuaführunffabeiBpiel 2

l i'ine solution! 2, -Bromopyridin (12.3 g) in dry üther (80 ml) of a 1.55 M solution of butyllithium in hexane (30 ml) at -78 ⁰ C was added .. The Mixture was stirred for one hour at -78 ° C and treated with a solution of 1- (4-chlorophenyl) cyclobutanecarbonitrile (8 g) in ether (8 ml), whereupon the mixture was allowed to rise in temperature to ambient temperature equalize. After 1 hour, a solution of sodium borohydride (3 g) in dry diethylene glycol dimethyl ether (130 ml) was added and the mixture was heated to 95 ^° C. over 2 hours. Then water (100 ml) was added and the mixture was extracted with ether, then the acid extract was washed with ether, alkalized with aqueous sodium hydroxide solution and extracted with iitherite. The üther-

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Extract was filtered through diatomaceous earth, dried, and the solvent was eliminated by evaporation. The residue was distilled in the range of 168 ... 180 ⁰ C at 0.2 in Hg pressure to give an oil, which was dissolved in üther. Hydrogen chloride gas was passed through the ethereal solution and the resulting. Precipitation was with propane-2-d. heated / 'i- (4-Chloi "- phenyl) cyclobutyJL7- (pyrid-2-yl) methylamine dihydrochloride (m.p. 240 _eO o245 ⁰ G) (dec.)) to give.

In a manner similar to that described above, the following compounds were made:

2a) / T- (4-chlorophenyl) cyclobutyl-7 (pyrid-3-yl) -ciethylamine dihydrochloride (mp 275 »o.280 ⁰ G)

2b) / T- (4 ~ hlorophenyl ^ü) cyolobutyl7 (pyrid-4-yl) methylamine dihydrochloride ¹ (lard point 260 ... 265 ⁰ G).

Exercise Example 3

h'ine solution of 2-bromopyridine (4.8 g) in dry iither (30 ml) was added (18 ml) was added at -78 ⁰ C under stirring a 1.7 M solution of butyllithium in hexane ·. After one hour at that temperature, a solution of 1- (4-oleophenylyl) cyclobutanecarbonitrile (4 g) in a mixture of dry jitter (80 mL) and dry tetrahydrofuran (10 mL) was added and the temperature allowed to reach ⁰ C to rise. After cooling to r ^{2 0} G, methanol (20 ml) was added dropwise followed by water (30 ml), and the aqueous mixture was extracted with either.

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and the uterine extract was washed, dried and evaporated to give / TC ^ -biphenyl-cyclobutyl / cpyrid-cymethanimine in the form of an orange oil. The U1 was dissolved in propan-2-d (200 mL) and heated under reflux conditions with matrium borohydride (2.0 g) for five hours. Then, water was added and the propan-2-ol was removed by jivaporating. The aqueous residue was extracted with ISther. Chriorwasaeratoffgaa was then introduced into the dried extract to give a gum, which in turn was heated with propan-2-ol to give a white solid which in turn was recrystallized from a mixture of methanol and propan-2-d to / T- (4-biphenylyl) -cyclobutyl7- (pyrid-2-yl) methylamine dihydrochloride hydrate (m.p. 240 ⁰ G (zerso)) to give. -

In a manner similar to that described above, the compounds of formula XVI listed in Table 1 were prepared »

Table 1

Ar

XVI

Ausf sspl • * ™ e AT .. · > 3-pyridyl η ' Melting point ⁰ G Anmenkungen 0 I ro 3a 3-trifluoromethylphenyl ^3-1 'hienyl 2 265 ⁰ C (decomp.) 07 G / ro t 3b 4-chlorophenyl 2-pyridyl 1 253 ... 255 ⁰ G (1.) (2) VJl VJl ro OD 3c 4-chloro-3,5-dimethylphenyl 2-pyridyl. 2 238c..242 ⁰ C (3) · 3d 3,4-dichlorophenyl 3-pyridyl 2 271 ... 273 ° C (decomp.) (3) 3e 4-methylthiophenyl 2-'J- ¹ hienyl 1.1 253oc, 257 ⁰ C (3) (4) (5) (6) (8) vi> «e _Λ 3Ϊ 4-5 ¹ IuOr ophenyl 2-pyridyl 1 230.O.233 ⁰ G (4) (5) (8) (9) VD CD J = » 3g Of 6-chloro-2-naphthyl 3-pyridyl 2 208o.o212 ⁰ G (3) (4) - (5) " 3h 4-chloro-2-fluorophenyl 2 ' 276c.279 ⁰ C he »(8) ^ VJl ro

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Notes to Table 1 :

(1) Imine purified by distillation and isolated as its hydrochloride salt

(2) the sodium labohydride was added in diethylene glycol dimethyl ether

(3) The sodium labohydride was added in ethanol

(4) Carbonitrile added in othether solution

(5) after reduction, the solvent was removed by distillation and the residue was dissolved in Ji'ther

The xither solution was then washed with water.

(6) Salt contains 0.67 mol of water

(7) Heinihydrate - recrystallized from propan-2-ol

(8) butyl lithium at -70 ⁰ G added; Methanol at -40 ⁰ C added

(9) Product recrystallized from a mixture of ethanol. and petroleum ether (boiling point 60 °, »80 ^° C.).

Embodiment Example 4 -

1-Methylpyrazöl (4.8 g) was a mixture of dry Ilther (60 ml) and a 1.7 M solution of ^ utyllithium in hexane (30 ml) under nitrogen at a temperature of less than 5 ⁰ C was added. Next, Ν, Ν, Ν ¹ , N '-'l'etramethylethylenediamine (TMiSDA) (8.3 g) was added; the mixture became O ₀ . _e 5 ⁰ G stirred for 1 h45 min, then with 1 ~ (4-chlorophenyl) -cyclobutancarbonitril (6.0 g) and then 90 min at a temperature in the range of 0 ... 5 ⁰ G stirred. Now, water was added, after which the reaction mixture was extracted with ether. The li'xtrakt was washed, dried and evaporated to an oil

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give "in which it is / T- (4-chlorophenyl) cyclobutyl7- (1-möthyipyrazol ~ 5-yl) methanimine ₀ The imine was treated with a mixture of sodium borohydride (2 g) in diethylene glycol dimethyl ether (100 ml) under nitrogen at 95 ⁰ C stirred for two hours. The mixture was poured into water and extracted with ether.

The extract was washed, dried and evaporated to give a residue, which was dissolved in dry iither. Through the ethereal solution Ghlorwasserstoffgas was passed to cyclobutyl7 (1 methylpyrazol-5 ~ yl ~) methyl amine hydrochloride (melting point 316 _o .318 ⁰ G) to give a hydrochloride salt of / "T- (4-Ghlorophenyl) which Containing 1.25 mol of hydrochloride and 0.25 mol of water.

The compounds of formula listed in Table 2 were XVI as described above prepared in a similar manner, although the reaction between the heterocyclic compound and the butyllithium took place at 40 ⁰ G '' / urther modifications of the above method are carried Notes to Table 2 marked »

Table 2

Ar.

XVI

Ausf.- bspl.- Ar ^B 1 η Remarks Melting point of the HCl salt of the amine No. . I ro VJl 4a 4-chlorophenyl 5-Methyl fluoro-2-yl 1 (D (5) 218 ... 219 ⁰ C (zers.) I 4b 4-chlorophenyl 2-Puryl 1 (2) (5) 230 ⁰ C (decomp.) 4c phenyl 2-thienyl 1 (2) (5) 225 ... 230 ⁰ C (decomp.) 4d 4-biphenyl 2-thienyl 1 (1) (5) (6) 165 ... 170 ⁰ C 4e 4-chlorophenyl 1-methylpyrrole-2-yl 1 (3) (4) A £ 314-dichlorophenyl 1-methylimidazol-2-yl 2 (5) (7) (8) 259.0.261 ⁰ C

to hi »

vo ο · -3 - »vji ο vo

ro o ro

VJT VJl

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Remarks

(1) Imine isolated in the form of its hydrochloride salt

(2) -can. The solid containing Mn or an amine of imine was precipitated by adding a solution of acetic acid in c

(3) The product was separated by high pressure liquid chromatography as free base. The physical constants of the product were not determined

(A) As determined in the test described earlier, the imine intermediate had an ED 50 of less than 30 mg / kg.

(5) There was no IMEDA used

(6) The sodium borohydride was added in propane-2- &

(7) The sodium borohydride was added in ethanol

(8) The reaction between the heterocyclic compound and the butyllithium took place at 0 ⁰ G ₀

Example 5

A solution of 2-bromothiophene (.32.9 g) in dry ether (50 ml) was added dropwise to a stirred mixture of magnesium turnings (4.85 g) and ether (50 ml) under nitrogen. The wax-resolution whole magnesium, a solution of 1- (3,4-Dichlorophenyl) cyclobutanecarbonitrile was (30.6 g) in dry ether (200 ml) was added, followed das'Gemisch stirred at 20 ⁰ G for one hour and then a further Was heated under reflux conditions. Ea a pesticide was formed which is believed to be / T- (3,4-dichlorophyllyl) cyclobutyl-7 (thienyl-2-yl) methaniminylmagnesium bromide. This was collected by filtration.

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The material was dissolved in Jathanoi (200 ml) and a solution of sodium borohydride (10 g) in ethanol (500 ml) was added, whereupon the mixture was refluxed for four hours. The mixture was cooled and water (200 ml) was added followed by 5N hydrochloric acid. Daa ethanol was removed by evaporation and the aqueous solution was made alkaline by adding 5N sodium hydroxide solution. The aqueous layer was extracted with water and the extract was dried. In the etheriache solution Chlorwaaaeratoffgas was initiated to give / T- (3 »4-dichlorophenyl) cyclobutyl7 (thien-2-yl) methylamine hydrochloride (mp 238 _Ο . _Ο 242 ⁰ C) au give.

The compounds of i'ormel XVI listed in Table 3 were prepared in a manner similar to that described above.

Table 3

Ar

XVI

Ausfplspl.- Hr. Ar - ^R 1 - Remarks - η melting point he "ro / D / LO 0 I 5a 4-Ohlorphenyl 2-l ¹ hienyl 1 238 ... 240 975/12 255 ro CD 5b 4-chlorophenyl 1-Methylimi'dazol-2-yl (1) (2) (4) O 93 ... 94 228 I 5c 2-Iaphthyl ' 1-methylimidazol-2-yl CD (3) (4) O 126 ... 129 5d 4-methylphenyl 2-thienyl (5) 1 228Ό0.23Ο 5e 4-methoxyphenyl 2 ^ 3) hienyl 1 192..0195 5f 4-bromophenyl 2-thienyl 1 235o..237. 5g 4-iodophenyl 2-lhienyl 1 228 ... 230 VO , VD CD-fc » _

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Remarks

(1) I-methylimidazolylmagnesium bromide was prepared by a modification of the method described by R, Kalish et al., J. Het. ^u henu 1953 20, Se 702 to 707 described process ago

\ represents. '

(2) The free base was recovered by distillation (boiling range 160o..170 ⁰ G at 0.1 mm Hg) and recrystallized from cyclohexyn α

(3) The sodium borohydride was dissolved in diethylene glycol dimethyl ether.

(4) Grighard reagent prepared in tetrahydrofuran solvent.

(5) Iminylmagnesium bromide was not isolated as a pesticide. The ether was removed by means of evaporation, and the residue was heated C for one hour under a nitrogen atmosphere at 90 ₀ · 95 ⁰ »behandäLte The residue was dissolved in ethanol,"

Embodiment 6

A solution of 4-methylthiazole (4.95g) in ether (5ml) was added to ethylmagnesium bromide, which under a nitrogen atmosphere was made up of magnesium twisted pens (1.2g) and ethyl bromide (5.5g) in ether (40ml). "A yellow precipitate formed, which dissolved in the ether when replaced by tetrahydrofuran (70 ml)." Then 1- (4-chlorophenyl) cyci-butanecarbonitrile (6.0 g, after which the solvent was passed through) was formed Toluene was replaced and the geraisch was heated at 90 ⁰ G for two hours.Now water and 2N sodium hydroxide solution were added, after which the reaction mixture was extracted with ether

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has been. The mixture was dried, the solvents were removed by evaporation. The residue was dissolved in ether and hydrogen chloride gas was bubbled into the solution to give a pale yellow solid, which is believed to be / T ~ (4-chlorophenyl This salt was heated to 95 ° C. with a solution of sodium borohydride ( ² g) in diethylene glycol dimethyl ether (100 ml) for two hours, then water and 2K sodium hydroxide were added. "LÖaung added and the reaction mixture was extracted with Üther ₀ the extract was dried, the solvents were evaporation means removed the residue was dissolved in üither} GhlorwaaserQtiofi'ga ^ was introduced into the solution to give a yellow solid This solid was dissolved. converted to the free base, which was purified by column chromatography on a Florisil column containing the mixture of ether and cyclohexane was eluted to give (4-chlorophenyl) cyclobutyl-7 (4-methylthiazol-2-yl) -methylamine, which was dissolved in a hydrochloride salt containing 1.5 mol of hydrochloride (melting point 230 °). , 232 ⁰ G (decomp.)) By dissolving the free base in ether and passing hydrogen chloride gas through the solution, ''

Ausführungsbe game 7

The product of embodiment 5 (a) in the form of its free base (2.0 g), 98% formic acid (8 ml) and 37 * 40 _o / £ aqueous formaldehyde solution (16 ml) were added at one hour stirred 20 ⁰ G and then held for one hour at 55 _o .60 ⁰ G, whereupon the volatiles at 95 ⁰ and G

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The residue was alkalized with aqueous sodium hydroxide solution and extracted with rither. Hydrogen chloride gas was bubbled through the dried ethereal solution to thereby precipitate an oil. The solvent was evaporated, the residue was triturated with dry ether and clarified by filtration. The filtrate was evaporated and the residue was triturated with dry acetone to give N, M-dimethyl- / i "- (4-chlorophenyl) cyclobutyl. (thien-2-yl) methylamine hydrochloride (mp 185o.o 190 ⁰ G).

Embodiment 8

"Kssigsäureanhydrid (5 ml) was added to a mixture of the product of Example 5 (a) in the form of its free base (3 g) and minced (5 g,), and the resulting mixture was stirred for 5 min Sodium hydroxide (5N) was added and the resulting basic mixture was extracted with ether. The extract was washed with water, dried and then removed by evaporation to give a residue, which in turn was treated with petroleum ether (b.p. .80 ⁰ G) was triturated to give a solid, which (from petroleum ether boiling range .. G) was 80 _o 100 ⁰ crystallized to finally N-Aöetyl- / T- (4-chlorophenyl) cyclobutyl7 (thien-2- yl) methylamine to provide (melting point 105 · ⁰ ..108 C),

A solution of the N-acetyl compound (prepared in the above manner) (1.5 g) in dry tetrahydrofuran was added dropwise.

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weiae borane-dimethyl sulfide complex (2 ml) was added "The mixture was stirred for 30 min at 20 ⁰ C 'as well as 10 minutes at 40' .. 45 ⁰ C mulled the cooled reaction mixture was added water, which was then extracted with ether. Hydrogen chloride gas was introduced into the dried ether extract to give a solid, which was then heated with boiling ether. The non-resolving material was N-ethyl-2fT- (4-chlorophenyl) cyclobutyl-7- (thien-2-yl) methylamine hydrochloride (m.p. 204 o to 207 ° C).

Embodiment 9

A 1.7 M solution of butyllithium in hexane (30 ml) was added under nitrogen to a mulled solution of diisopropylamine (5.2 g) in dry ether (20 ml) at 20 ⁰ O. After 2Q min, the mixture was cooled to -20 ⁰ C and treated with a solution of ^f! 3- (3 g) in dry ether (50 ml) was added dropwise. Then, (6 g) was added to a solution of 1- (4- ^ü hlorphenyl) cyclobutanecarbonitrile lather in dry (20 ml). The temperature was maintained at 0 ^° C for 20 minutes. Now Natriuinborohydrid (2 g) in dry dimethylene glycol dimethyl ether (150 ml) was added and the mixture heated to 95 for 2 hours was ⁰ G long _β Water was then added and extract-ion carried a Jit forth. The extract was washed, dried and evaporated to give a residue, which was dissolved in ether. By introducing hydrogen chloride gas into the ether extract, T- (4-chlorophenyl) -cyclobutyl-7 (1,3-dithian-2-yl) -methylamine hydrochloride (mp 165.0.167 ⁰ G (zerse) was precipitated

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Embodiment 10

The product of Example 4 (b) (1.49 g) was dissolved in absolute ethanol (45 ml) and Raney nickel (approximately 3 ml) added. The mixture was stirred under a hydrogen atmosphere for 2 h 3 min, then the reaction mixture was filtered and the solvent was removed by evaporation. The residue was dissolved in dilute hydrochloric acid; the solution was made alkaline, and a white solid was formed, which was extracted into ether. The extract was dried to give _j /T- (4-chlorophenyl) -cyclpbutyl] -7tetrahydrofur-2-yl) methylamine as an oil (physical constant not determined),

Ausführunpabeispiel.11

The product of Example 3 was mixed in its free base with _# methyl formate, and the mixture was stored at ambient temperature for 4 days. A gum, which was triturated with petroleum ether with heating, formed N-pyryl / T - (4-biphenylyl) -, cyclobuty _i l7 (pyrid-2-yl) methylamine (m.p. 101 ⁰ G).

Embodiment 12

The product of Example 3 (d) in the form of its free base (3 g) and cyclopentanone (1.65 g) were mixed at room temperature and then heated to 140 ^° C. with stirring for 19 hours. The mixture was then added to room temp.

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cooled, dissolved in the minimum amount of ethanol (200 ml) and treated with a suspension of sodium borohydride (2 g) in ethanol (2o ml). The mixture was refluxed for 2 hours, then allowed to stand at room temperature for 16 hours, and then the solvent was removed. The residue was diluted with water, acidified with 2N hydrochloric acid, alkalinized with 2N aqueous sodium hydroxide and extracted with ether. The extracts were washed and dried and the solvent was removed to leave an oil which was purified by chromatography to give a pale brown gum, which was taken up in iither and saturated with hydrogen chloride to give N- / i ~ (3 »4 -Dichlorophenyl) cyclobutyl / (2-pyridyljmethylcyclopentylaminsesquihydrochlorid (melting pmikt 120. o. 122 ⁰ C) to give.. '

Claims (2)

Process for the preparation of arylcyclobutyl-methylamines of the formula I wherein R- corresponds to a heterocyclic ring with one or more heteroatoms selected from N, O and S}. _v wherein Rp, R and R, which may be the same or different, are H, halogen, trifluoromethyl, hydroxy, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms or phenyl or in which R ₂ and R 1 together with the carbon atoms to which they are attached form an optionally substituted second benzene ring} and their pharmaceutically acceptable salts, characterized in that one of the following reactions is carried out a) reductive amination of ketones of the formula III '*; Ά 9.> ί Ά R COR. (III) by the reaction of the ketones of formula III with an ammonium salt as well as a reducing agent j b) Reduction of compounds of the formula I? (IV), wherein ba) Z corresponds to a group of the formula -CR. "HÖH or an ester or ether derived therefrom, or bb) Z corresponds to a group of the formula -CR ₁ NYNY in which Y corresponds to a group derived from a Grignard-Reägens of the formula MgCl or MgBr or else Li which was derived from an organolithium compound. c) decarboxylative rearrangement, for example, using iodosobenzene bistrifluoroacetate or a Hofmann reaction using bromine in alkaline solution - of amides of formula V. , COMH R- (V) d) decarboxylative rearrangement of acyl azides, which by the reaction of acid chloride & dender the formula VI .COCl R- (VI) R to be formed with sodium azidej e) Reaction of nitric acid with carboxylic acid of formula VII CHR ^ COOH R. (VII) f> reductive amidation of ketones of formula III by reaction of the ketones of the formula III with f-) formamide and formic acid or fp) Ammoniumformi? and formic acid and subsequent hydrolysis. 2. The method according to item 1b, characterized in that the reduction is carried out by a 'reducing agent which is selected from sodium borohydride, sodium cyanoboron hydride or lithium aluminum hydride.'